DE1018863B - Process for the manufacture of saturated or unsaturated oxygenated steroids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN j ^ £ Vcft \ PATENT OFFICE

kl. 12 ο 25/05

INTERNAT. KL. C 07 C

EXPLAINING PUBLICATION 1018 863

SIGN UP DAY:

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL:

R 18742 IVb / 12 ο 3 JANUARY 1955

NOVEMBER 7, 1957

It is well known that aldosterone has the following formulas, which are apparently in equilibrium to:

HIGH,

CHO CO-CH ₂ OH

13 i

O =.

O CH-

-OH
CO-CH ₂

-OH

CH.

3 1

O =

As can be seen from this, aldosterone and its functional derivatives are dioxigenated in the 3, H position Pregnane compounds or functional derivatives thereof, the remainder of which in the 13-position is a free or functional represents modified aldehyde group.

Patent application R 15735 IVb / 12o describes a process for the preparation of oxygenated steroids described, which is characterized in that halides of ethyl acids of the general formula

Method of manufacture

of saturated or unsaturated

oxygenated steroids

Applicant:
Dr. Tadeus Reichstein, Basel (Switzerland)

Representative: Dipl.-Ing. E. Splanemann, patent attorney,
Hamburg 36, Neuer Wall 10

Claimed priority:

Switzerland from January 15, February 5, February 25,
March 5 and May 18, 1954

Dr. Tadeus Reichstein, Dr. Albert Wettstein,

Dr, Georg Anner, Dr. Jean-Rene Billeter,
Dr. Karl Heusler, Basel, Dr. Robert Neher, Binningen,

Dr. Julius Schmidlin, Basel,

Dr. Hellmut Ueberwasser, Riehen,

and Dr. Peter Wieland, Basel (Switzerland),

have been named as inventors

R ₂ -CH ₃

CO shark

The present invention relates to another method of preparing the same compounds, namely of saturated and unsaturated steroids of the general formula

R ₁

R ₂ -

CH ₁

R ₃

^ CO - CH ₉ - R,

in which R ₁ and R _{2 are} functionally modified oxy or oxo groups or free oxo groups, R _{3 is} a functionally modified oxygenated methyl group and Hal is a halogen atom, is reacted with diazomethane, the diazoketones obtained are treated with an acid and optionally functionally modified oxy, oxo or carboxyl groups converted into free groups. According to this process, aldosterone or compounds closely related to it can be produced.

R ₁ -L

in which R ₁ and R _{2 are} free or functionally modified oxy or oxo groups, R _{3 is} a free or functionally modified oxygenated methyl group and R _{4 is} a free or esterified oxy group, which there-

709 759/426

3 4

is characterized by the fact that saturated or un- this cleavage is advantageously carried out in an anhydrous medium saturated pregnane compounds of the general formula approximately equimolar amounts of an alkali metal alcohol

lates, e.g. B. sodium methylate or ethylate made. A gentle way of working up in this process step consists in the fact that the reaction mixture is removed instead of in water in an aqueous buffer solution, e.g. in one containing 1 molar equivalent of monosodium phosphate aqueous solution, pours.

The 21-halides can be converted by reaction with ίο salts of organic or inorganic acids, for example acetic acid, propionic acid, butyric acid, trimethyl acetic acid, crotonic acid, oenanthic acid, palmitin in which R ₁ , R ₂ and R _{3 have} the meaning given above acid, benzoic acid, phenylacetic acid, ß-Cyclopentyl possess, in a known manner with an oxalic acid ester propionic acid or phosphoric acid, is converted into the corresponding, converting the 21-oxalic acid esters obtained in the form of their 15 21-ester. The 21-esters obtained in this way are treated like enol salts with a halogen; the 21-halides formed can also be obtained by hydrolysis e.g. B. 21-halo-21-oxalic acid ester with acid cleavage with alkaline agents, for example with bicarbonates, throws, the 21-halides obtained are converted into the 21-ester or into the 21-oxy compounds. 21 -oxy compounds transferred and optionally radio- The transfer according to the method functionally

Functionally modified oxy, oxo or carboxyl groups 20 converted oxy and oxo groups into free groups sets in freedom. be carried out according to methods known per se.

An oxygenated methyl group is a carbinol, aide. B. ketals and acetals, namely open-hydrated or carboxyl group. Among compounds with chain like cyclic, ζ. B. Ethylene ketals, by befunctional modified oxy, oxo or carboxyl treatment with mineral acids or sulfonic acids groups one understands z. B. esters, thioesters, enol esters, 25 room temperature, advantageous in the presence of a Ke ether, Enol ethers, thio ethers, acetals, ketals, mercaptals, tons, such as acetone or pyruvic acid, or through Split lactones, cyclo-hemiacetals, thiol and thione esters, gentle warming with dilute acetic acid, amines, hydrazones or semicarbazones. Under the same acidic conditions, enol feedstocks are also used can split an aldehyde or carboxyl group ether or tetrahydropyranyl ether. Benzyline 13-Steüung with an oxy group in H-position 3 ° ether can also easily be counter-acetalized with hydrogen or be lactonized. The hydroxyl group was a catalyst, e.g. B. Palladium, on a carrier 18-11-Cyclohalbacetals can also functionally degrade, such as animal charcoal or alkaline earth carbonates, converted, e.g. B. esterified with organic acids, ζ. Β. be split.

with acetic acid or benzoic acid, or etherified, the pregnane compounds obtained are saturated

z. B. with benzyl alcohol. Double bonds can e.g. B. 35 or unsaturated 20-oxoin oxygenated in the 18-position 4 (5) or 5 (6) position. There can be 21-oxypregnane or their esters, which either themselves Both racemic and optically active compounds are physiologically active or are physiologically active be turned. have effective connections transferred. You can

The reaction with oxalic acid esters, e.g. B. an oxal therefore as a remedy or as an intermediate to their Acid alkyl esters, such as -methyl-, -äthyl-, -propyl- or 40 production are used.

-benzyl ester, in the presence of a basic condensate- The products of the process can be approximately as follows

sation means carried out. Can be further converted as a condensing agent: Is in 13-position a into a alcoholates are particularly suitable, ζ. B. Sodium-free or functionally modified aldehyde group over methylate, Sodium ethylate or potassium tert-butylate. feasible remainder, such as a free or functionally

If one wants to convert carboxyl, especially lactone, or carbinol lengths into optically active process products, the corresponding optically active group can be present, and the starting compounds of its kind can be used measured means obtained in the following manner, such as B. Reducing agents or oxybeing: After completing the first stage of the pre-agent, let it take effect. For example Lying process obtained racemic 21-oxalo-18,11-lactones according to the process of the patented malic acid ester are produced by mild alkaline hydrolysis in 50 dung R 18741 IVb / 12 ο in 11-oxyaldehydes or their the free 21-oxaloic acids converted, these converted with optically cyclo-hemiacetals or 11, 18-diols, under active bases such as strychnine or brucine, among which also aldosterone and its functional derivatives speaking salts implemented, the diastereomeric grain are to be counted.

component separated by fractional crystallization and the conversion of free oxy groups into oxo

from the salts the antipodes of the 21-oxaloacids in 55 groups takes place z. B. by oxidizing agents such as Freedom set; by mild hydrolysis, chromic acid is finally converted into glacial acetic acid, or by dehydrating agents, the 21-oxalic acid residue is split off again, which leads to the same as heating with copper powder, action of metallic earths optically active methyl ketones. alcoholates or phenolates in the presence of ketones,

The enol salts formed of the 21-oxaloic acid esters are like acetone or cyclohexanone.

with chlorine, bromine or iodine or those emitting halogens 60 A double bond must be introduced in the 4 (5) position Means, e.g. B. N-haloamides or imides treated. this can be done in the usual way, e.g. B. by HaIo-Particular iodine is suitable for this implementation. One generation and subsequent removal of hydrogen halide it is expedient to do so in the presence of a lower tung.

aliphatic alcohol such as methanol or ethanol. Obtained racemates can be at any level

For acid cleavage, the 21-halogen-65 is subjected to their antipodes according to methods known per se 21-oxaloic acid ester of the action of an alkaline split.

By means of e.g. B. an alkali metal hydroxide or alcohol The starting materials are new. You can z. B. after

lates. If other alkali-sensitive substances are present, follow the process of patent application R 15734 IVb / 12 0 Groupings in the molecule, e.g. B. one (18 -> - H) - produce. You can also choose from saturated and in part Lactone group or 18,11-cyclo-hemiacetal group, becomes 70 unsaturated, 17- or 17- or

20-keto steroids or dioxigenated in the 3,11 position 13, ly-Seco-steroid-l ?, 13-lactones according to the patent application R 15735 IVb / 12 ο described method.

co CH ₃ CO -CO OX OX ' NaOH co— CH ₂
TT

The process according to the implementation of the starting materials with oxalic acid esters and the further stages of the process can be illustrated by the following equation:

CO-OX CO-CH = CONa

Cl

R ₁ -

CO-CH ₉ -R _d

The following examples explain the process according to the invention. Between part by weight and part by volume exists the same relationship as between grams and cubic centimeters.

example 1

Gd to a mixture of 8.25, l-Zl ⁵ -3-ethylenedioxy-11 / 3,18-dioxy-20-oxo-pregnene, 4.7 g of freshly prepared dry sodium methoxide and 9.4 g of dimethyl oxalate are 65 cm ^{3 given} dry benzene. The mixture is then left to stir at room temperature in a stream of nitrogen for 24 hours. After adding ice and carefully acidifying, it is immediately shaken out with ether. The ethereal solution is extracted with 173 cm ^{3 of} 1N potassium hydroxide solution and the aqueous-alkaline solution is left to stand for 1 hour at room temperature. It is then carefully acidified while cooling with ice and immediately shaken out again with ether. From the residue of the dried and evaporated ethereal solution, crystallization gives d, 1A ^B -3-ethylenedioxy-11 / 3,18-dioxy-etienoyl-pyruvic acid in colorless crystals.

2.31 g of the acid obtained are ^{mixed with 600 cm 3 of} water containing 25 g of disodium hydrogen phosphate, whereupon a suspension of 1.27 g of iodine in 120 cm ^{3 of} ether is slowly added with stirring. After the color of the iodine has disappeared, a solution of 1.2 g of potassium hydroxide in 36 cm ^{3 of} water is added and the mixture is left to stir for 24 hours in a stream of nitrogen with exclusion of light. ^{8 g of dry potassium acetate and 100 cm 3 of} acetone are added to the residue of the separated, dried and evaporated ethereal solution. After refluxing for one hour, the acetone is evaporated off in vacuo and the residue is extracted several times with ether. After washing with water, drying and evaporation of the ethereal solutions, crude d, l-zl ^B -3-ethylene-dioxy-11 / ?, 18-dioxy-20-oxo-21-acetoxy-pregnen, which is pregnen by chromatography pure in aluminum oxide.

0.25 g of the ketal are stirred overnight with a solution of 0.05 g of p-toluenesulfonic acid in 20 cm ^{3 of} acetone. After dilution with saturated sodium chloride solution and shaking out with chloroform, the d, 1-18-oxycorticosterone acetate is obtained as a colorless amorphous residue from the washed, dried and evaporated chloroform solutions. Compared to silver diammine solution, the product shows a strong reducing power and, dissolved in fine spirits at 238 ΐημ, an absorption maximum (ε = 12300).

The saponification of the acetate obtained is carried out as follows:
A solution of 0.3 g of potassium bicarbonate in 10 cm ^{3 of} water is added to 0.25 g of crude d, l-IS-oxycorticosterone acetate and 40 cm ^{3 of methanol while stirring in a stream of nitrogen.} After standing for 48 hours at 20 ° in the evacuated vessel, it is concentrated in vacuo to a fifth of the original volume and extracted with chloroform ether (1: 3). The residue of the organic solution, washed with water, dried and evaporated in vacuo, is chromatographed on 10 parts by weight of aluminum oxide (activity II, neutral according to Brockmann), the d, 1-18-oxycorticosterone being obtained as a pale yellow lacquer. In the IR spectrum it shows the characteristic bands at 2.75 μ, 2.92 μ, 5.81 μ, 5.98 μ and 6.14 μ. The compound reduces silver diammine solution instantly and has a strong absorption maximum at 240 πιμ (ε =

7o 10800).

7 8

The starting material can be prepared according to the method of the water bath. After cooling, the reaction is patent application R 15734 IVb / 12 ο. mix in a vacuum with the addition of 20 parts by volume

. -io water evaporated to a small volume, then

Example I again added water and with ether methylene chloride

A mixture of 1.932 parts by weight (18 - * - 11/3) - 5 mixture (3: 1) shaken out. The one with ice-cold 0.5n-

Lacton of the d, l- «d ⁵ -3, S-ethylenedioxyd-II / S-oxy ^ O-oxo-sodium carbonate solution and water and washed with

Pregnen-18 acid in 90 parts by volume of benzene and 40 parts by volume of sodium sulfate, dried extract is evaporated

share an immediately previously prepared benzene and the almost completely crystallized residue one

Solution which is subjected to 0.2N sodium methylate and to oxalic partition chromatography on cellulose,

acid dimethyl ester is 0.5 molar, is 16 hours under io. Formamide is used as the stationary phase and the mobile phase

Stirred exclusion of moisture at room temperature. Cyclohexane-benzene mixture (1: 1). The first eluates

It is then poured into 80 parts by volume of 1 molar sodium consisting of weakly polar, in the ultraviolet absor-

dihydrogen phosphate solution and shakes with chlorobating impurities. In the further elution

form-benzene mixture (1: 1). That followed with water is initially followed by a subordinate amount (18 - »- 11 /?) -

Washed and dried with sodium sulphate extract ¹ S lactone of d, 1- / 1 * -3, 20-dioxo-II /? - oxy-pregnen-18-acid

is evaporated under reduced pressure and that of the F. 217 to 219 ^C and then eluates of strong

completely crystallized residue in a high vacuum reducing power to alkaline silver diamonds

freed from dimethyl oxalate at 40 °. By releasing it. These latter are united and out

crystallize the crude product from anhydrous ether using acetone-ether (about 1: 3)

recrystallized using methylene chloride as a solubilizer, 20 methylene chloride as a solubilizer,

in the middle one obtains the (18-> · ll / 3) -lactone of the d, 1-zl ⁵ - The of the thus obtained (18- »- Ilj8) -lactone of the d, 1-zl ⁴ -

3,3-Ethylenedioxy-II /? - oxy-20-oxo-pregnen-18-acid-21-3,20-Dioxo-II / 3-oxy-21-acetoxy-pregnen-18-acid vom

oxaloic acid methyl ester in needles from F. 199 to F. 244.5 to 247 "in chloroform solution

202 ° (decomp.). Infrared absorption spectrum is correct in every respect

To a cooled to 0 ° suspension of 0.945 overall 25 _m it that of the 21-monoacetate aldosterone by

parts by weight (18 -> ■ ll /?) - lactone of the d, 1-Δ ⁵ -3, 3-ethy-oxidation with chromium trioxide obtained natural

lendioxy-11 / J-oxy ^ O-oxo-pregnen-lS-acid ^ l-oxaloic acid antipodes match.

methyl ester in 24.0 parts by volume of methanol is added

with exclusion of moisture and stirring, 4.00 volume acetoxy group can also be used.

parts of a 0.5n methanolic sodium methylate solution 3 parts by weight of crude (18 -> - ll / 3) lactone of d, 1-Δ ⁵ -

and, after a clear solution has formed, 3, S-ethylenedioxy-II / S-oxy ^ O-oxa ^ l-acetoxy-pregnen-

within 1 minute initially with 13.5 parts by volume of an 18-acid with 12.1 parts by volume of tetrahydrofuran

methanolic 0.15 molar iodine solution and pour further and the mixture after adding 4.03 vol-

Stirring for 15 minutes with a second portion of partially aqueous 4N perchloric acid until complete

4.00 parts by volume of 0.5N methanolic sodium methylate 35 dissolution of the starting material. To

solution. The mixture is then 3 ¹ Z ₂ hours ostündigem storing in the dark mixture is cooled in ice

stirred at 0 ° and then the deposition of iodine ketone water off, neutralized with 32.2 parts by volume of 0.5N Na

by adding 5.0 parts by volume of 0.5 molar sodium trium hydrogen carbonate solution and distilling the tetra-

dihydrogenophosphate and 40 parts by volume of 50 ° / ₀ sodium hydrofuran off in vacuo; the remaining aqueous

aqueous methanol completed. The suspension from the mother 40 is extracted with methylene chloride, the

alkaline suction filtered, finely crystalline, colorless substance extract with O, 2N sodium carbonate solution and water

represents the (18 - »- ll /?) - lactone of the d, l- /! ⁵ -3, 3-ethylene washed, dried with sodium sulfate and concentrated

dioxy-II / 3-oxy-20-oxo-21-iodo-pregnen-18-acid; she steams. The crystalline residue is subjected to the

expediently, without further purification, the following partition chromatography on cellulose with formamide

Subjected to reaction with potassium acetate. 4-5 as the stationary phase and benzene as the mobile phase. The first

The resulting crystallized (18 - »- 1 IJS) -LaCtOn of the eluates contain a weakly polar, in the ultraviolet -

d, l-Zl ⁵ -3,3-ethylenedioxy-II / S-oxy-20-oxo-21-iodine-pregnene-sorbing by-product. As the egg progresses

18-acid is then rinsed with 60 volumes by volume, followed by a subordinate amount of the

Acetone too fresh from 5.01 parts by weight of potassium hydrogen- already described above (18 -> - ll /?) - lactones of the

carbonate and 3.00 parts by volume of glacial acetic acid prepared 50 d, l-Zl ⁴ -3,20-Dioxo-II / S-oxy-pregnen-18-acid of F. 217

Potassium acetate given and the whole thing for 1 hour in stick up to 219 ° and finally fractions as the main ingredient

Substance atmosphere cooked on the water bath. After that of strong reducing power against alkaline

Most of the acetone is cooled by a silver diammine solution. From the latter one obtains

evaporate in vacuo, the residue water by recrystallization from acetone - ether the (18 - * - 11 / J) -

added and then with ether-methylene chloride (3: 1) 55 lactone of d, l-Zl * -3, 20-dioxo-11/3, 21-dioxy-pregnen-

extracted. The one with 0.1 n sodium hydrogen carbonate and 18 acid from 230 to 235 °.

Water-washed extracts are combined, dried with a solution of 0.655 parts by weight of the above sodium sulfate and evaporated. One over-described (18 - »- II /?) - Lactons des d, l-Zl ^s -3, 3-Äthygieß the residue with 25 parts by volume of benzene and alder-dioxy-1 l / I-oxy ^ O-oxo- pregnen-IS-acid ^ l-oxaloic acid warms 3 minutes to the boil. Evaporation in a methyl ester of 60 in 105 parts by volume of a methylene chloride vacuum gives a crystalline residue. The ether mixture (1: 3) is shaken with 14 parts by volume of 1N castell of the crude (18 - »- II / S) lactone of the d, l-zI ⁵ -3, 3-ethylium hydroxide solution. As soon as the enol potassium salt which separates out in solid lendioxy-ll | # -oxy-20-oxo-21-acetoxy-pregnen-18-acid form is completely in. The substance is completely halogen-free; alkaline solution, the layers are separated and the silver diammine solution is instantly reduced by it. 65 aqueous phase immediately with 12.5 parts by volume of methyl 0.793 parts by weight of crude (18 - »- 11ß) lactone of the lene chloride-ether mixture (1: 3) and acidifies it after d, l- <d ⁵ -3, 3 -Ethylenedioxy-II / 3-oxy-20-oxo-21-acetoxy- adding ice with 2 molar phosphoric acid. The pregnene-acid 18-poured over with 40 parts by volume of precipitated crude acid is taken up in chloroform, 50 ° / ₀ aqueous acetic acid and heated under over- the extract washed with water, dried and introduction of nitrogen for 45 minutes in the boiling 70 evaporated. Crystallization from methylene chloride

9 10

the pure (18 - »- ll /?) - lactone of d, 1-Zf ⁵ - pregnen-18-acid is kept at a temperature of 195 to 198 ° and [a] jj = + 178 °

3, S-ethylenedioxy-llß-oxy ^ O-oxo-pregnen-IS-acid- (α = 0.95 in chloroform) converted.

21-oxaloic acid with a melting point of 188 ° to 190 ° (decomp.). The (18 -> 11 /?) - lactone of the d-Zl ⁴ -3, 20-DiOXo-II ₁ S-

A solution of 0.0459 weight oxy-pregnen-18-acid prepared at 40 ° can be divided by heating with (18-v U / 3) -lactone of d, l-Zl ⁵ -3, 3-ethylene-5 Methylethyldioxolane in benzene into the (18 -> - ll / 5) -Lac-

dioxy-ll / S-oxy-20-oxo-pregnen-18-acid-21-oxaloic acid clay of d-2l ⁵ -3, 3-ethylenedioxy-l 1 ß-oxy-20-oxo-pregnen-

and 0.0335 parts by weight of strychnine in 1.2 parts by volume of 18-acid, which in all chemical properties

Boiling acetone is added to methylene chloride and the mixture mentioned at the beginning of this example is used

displaces the methylene chloride by distilling off. and racemic lactone used as starting material From the solution, which has been concentrated to about 1 part by volume, io matches; by implementing according to the in this

the strychnine salt of the (18 - * ll ^ -lactone of the example given, one obtains the

lA ⁵ -3, S-Äthylendioxy-llß-Oxy ^ O-oxo-pregnen-lS-acid- (18 h- 11 / S) -lactone of the dJ ⁴ -3, 20-Dioxo-ll / S-oxy-

21-oxaloic acid from 203 to 204 ° (dec.) And [d] _D = - 47 ° 21-acetoxy-pregnen-18-acid from 198 to 200 ° and

(c = 1.0 in methylene chloride) in almost quantitative [d \ _D = + 118 ° (α = 0.61 in chloroform). The substance is yield off. The strychnine salt of d-acid remains in the 15 with that from d-aldosterone-21-monoacetate by oxy-

Mother liquor. dation with chromium trioxide prepared natural anti

A solution of 0.0268 parts by weight of the strychnine pod is identical.

salt of the (18 -y ll /?) - Lactons of the l-Zl ⁵ -3, 3-ethylene- The starting material can be, for example, from the in the

dioxy-lljS-oxy ^ O-oxo-pregnen-lS-säure ^ l-oxaloic acid described in patent application R 15734 IVb / 12 ο 10 parts by volume of methylene chloride is successively at 0 ° 20 (18-VlI (S) -LaCtOn der d, lA ⁵ - ^ie '-3, 3-ethylenedioxy-

with 5 parts by volume of 1,5N-phosphoric acid, three times with 11 ^ -oxy-20-oxo-pregnadiene-18-acid with a temperature of 242 to 246 °

2.5 parts by volume of O, 6n-phosphoric acid and several times by catalytic hydrogenation of the 16, 17 double bond

Shaken ice water. Extracted before pouring away and cleavage of the 3-ketal grouping won,

one the aqueous extracts one after the other in two wide. .

ren separating funnels each with 2.5 parts by volume of methylene 25 Example 3

chloride. The methylene chloride solutions are then combined with a mixture of 0.96 parts by weight of the mixture, dried with sodium sulfate and evaporated. Acetylated obtainable according to the following reaction scheme. The (18 -> ■ 110) -lactone der \ -A ⁵ -3, 3-Ethy- 18, ll-Cyclohalbacetal des d, lA ^B -3, 3-Äthylenedioxylenedioxy-ll /? - oxy-20-oxo-pregnen-18-säure-21 -oxalosäure II / S-oxy-18, 20-dioxo-pregnens in 45 parts by volume of benzene as a colorless microcrystalline residue. 30 and 20 parts by volume of a freshly prepared benzene

A mixture of 0.0174 parts by weight of crude solution containing 0.2 mol of sodium methylate and 0.5 molar of oxalic (18 - * - 11 $ lactone of 1-Zl ⁵ -3, 3-ethylenedioxy-11-oxy acid dimethyl ester is, is stirred for 18 hours under 20-oxo-pregnen-18-acid-21-oxalic acid, 0.170 wt 40 minutes 35 dihydrogen phosphate solution and shakes with chloroform warmed up on the boiling water bath, then removed benzene mixture (1: 1). The washed with water cools and the neutral reaction product in methylene and sodium sulfate dried extract is under a chloride-ether mixture The extract is evaporated under reduced pressure and the residue is washed with 1N potassium hydrogen carbonate solution and with dimethyl oxalate in a high vacuum at 40 °, dried with sodium sulfate and evaporated it. By recrystallizing the crude product from ether, the (18 -> · ll / 5) -lactone of the anhydrous ether is obtained using methylene-Zl ⁵ -3, 3-ethylenedioxy-ll, S-oxy-20-oxo-pregnen- 18-acid chloride as a solubilizer, the acetylated one is obtained in colorless, shiny platelets. 18, ll-Cyclohalbacetal des d, l-Zl ⁵ -3, 3-ethylenedioxy-

A solution of 0.0200 parts by weight (18- * 11 / S) -113-oxy-18, 20-dioxo-pregnen-21-oxaloic acid methyl ester. Lactone of lA ⁵ -3, S-Äthylendioxy-llß-oxy ^ O-oxo-preg- 45 To a suspension cooled to 0 ° of 0.94 genes-18-acid in 0.70 parts by volume of tetrahydrofuran is added parts by weight of the acetylated 18, II-Cyclohalbacetal des with 0.35 parts by volume of 3N-aqueous perchloric acid, I-Zl ⁵ -3,3-ethylenediox3'-II / 3-oxy-18, 20-dioxo-pregnenmixed. After standing for 4 hours at room temperature, 21-oxaloic acid methyl ester in 24 parts by volume of methanol is added with 2.1 parts by volume of 0.5 N sodium hydrogen, carbonate solution is added with exclusion of moisture and stirring, and the tetrahydrofuran is distilled under 50 4 parts by volume of 0.5 N methanolic sodium methy- Adding 1.05 parts by volume of water in vacuo. The resulting suspension is shaken with methylene and mixed with a 13.5 volume chloride-ether mixture (1: 3) within 1 minute, and the combined parts of a 0.15 molar methanol are washed Iodine solution and extracts with 0.5 N sodium hydrogen carbonate solution and, after stirring for a further 15 minutes, with a second water, dry with sodium sulfate and evaporate the 55 portion of 4 parts by volume of 0.5 N methanolic sodium solution. The residue is obtained by methylate solution. The mixture is then recrystallized from acetone and ether (18 - * - 11 / S) - 3 ^χ / ₂ hours at 0 ° and then the lactone of l-zl ⁴ -3, 20-dioxo-11/3 is deposited -oxy-pregnen-18-acid of iodine ketone by adding 5.0 parts by volume with a temperature of 194 to 198 ° and [α] ρ = -176 ° (α = 1.0 in 0.5 molar sodium dihydrogen phosphate solution and 40Vo chloroform). 60 lumteilen 50 ° / ₀ aqueous methanol completed. In a completely analogous manner as above for the The finely crystalline strychnine salt of the (18 - »- II /?) Lactone of the 1-Zl ⁵ -3,3-ethy- colorless substance, sucked off by the mother liquor, is the acetylated 18,11- Cyclolendioxy-II /? - oxy-20-oxo-pregnen-18-acid-21-oxalic acid hemiacetal des d, l-zl ⁵ -3, S-ethylenedioxy-II / S-oxy-IS, 20-described is from that in the case of precipitation with strychnine constitutes dioxo-21-iodine pregnens; it is expediently set free, without the diastereomeric salt remaining in the mother liquor, the further purification of the subsequent reaction with potassium d-oxalic acid, by treatment with acetate.

Potassium hydrogen carbonate solution in the heat of the oxalo The obtained acetylated 18, ll-Cyclohalbacetal des

split off acid residue and the ketal obtained by means of d, 1-Zl ^B -3, S-ethylenedioxy-lljß-oxy-IS, 20-dioxo-21-iodine

Perchloric acid in aqueous tetrahydrofuran in the pregnens is rinsed with 60 parts by volume

(18 - + - U / S) -lactone of d- / l ⁴ -3, 20-dioxo-11/3-oxy- 70 acetone too fresh from 5 parts by weight of potassium hydrogen

carbonate and 3 parts by volume of glacial acetic acid prepared potassium acetate and boiled for 1 hour in a nitrogen atmosphere on a water bath. After cooling, most of the acetone is removed by evaporation in vacuo, water is added to the residue and then extracted with ether-methylene chloride (3: 1). The extracts washed with 0.1 N sodium hydrogen carbonate and water are combined, dried with sodium sulfate and evaporated. The residue represents the acetylated 18, 11-cyclo-hemiacetal of d, l-Zl ⁵ -3, 3-ethylenedioxyll / J-oxy-18, 20-dioxo-21-acetoxy-pregnens (d, 1-aldosterone-diacetate-3- ketal). The substance is completely halogen-free; alkaline silver diammine solution is instantly reduced by it.

0.8 parts by weight acetylated 18,11-Cyclohalbacetal of d, l-Zl ⁵ -3, 3-ethylenedioxy-LLSs-oxy-18, 20-dioxo-21-acetoxy-pregnens poured over with 40 volumes of 50 ° / ₀ aqueous Acetic acid and heated for 45 minutes on the boiling water bath while passing nitrogen over it. After cooling, the reaction mixture is evaporated to a small volume in vacuo with the addition of 20 parts by volume of water, then water is added again and extracted with an ether-methylene chloride mixture (3: 1). The extract, washed with ice-cold 0.5 N sodium carbonate solution and water and dried with sodium sulfate, is evaporated and the residue is chromatographed on 48 parts by weight of aluminum oxide of activity II (according to Brockmann). The first eluates with benzene petroleum ether (1: 1) are discarded; the last ones as well as those with benzene contain the acetylated 18,11-cyclo-hemiacetal of d, l-vd * -3,18, 20-trioxo-ll, 8-oxy-21-acetoxy-pregnens (d, 1-aldosterone diacetate) .

The d, 1-aldosterone can be obtained from the diacetate described above as follows: To a solution of 0.0083 parts by weight of d, 1-aldosterone diacetate in 1.5 parts by volume of methanol are added 0.01 part by weight of potassium ίο bicarbonate in 0.35 parts by volume of water and left after melting in vacuo for 48 hours at 20 ° stand. The methanol is then freed in vacuo and the aqueous residue is removed twice with 50 parts by volume each time Chloroform-ether (1: 3) extracted, the chloroform-ether solution washed with water, dried over sodium sulfate and evaporated in vacuo. That obtained d, 1-Λ * -3.18, 20-trioxo-llß, 21-dioxy-pregnen or its 18, 11-cyclo hemiacetal (d, 1-aldosterone) After dissolving from acetone, ether melts at 180 up to 182 °.

Is used in place of the acetylated 18,11-Cyclohalbacetals of d, l-Zl ⁵ -3, 3-ethylenedioxy-LLSs-oxy-18,20-dioxo-18,11-pregnens the acetylated Cyclohalbacetal of d, 1-Zl ⁴ - 3,18, 20-Trioxo-II / J-oxy-pregnen is used, the d, 1-aldosterone is also obtained in a similar reaction sequence.

The starting materials can be prepared according to the following reaction scheme:

O CO

-CO-CH,

Ethylene glycol + p-toluenesulfonic acid

ο

CH ₃

o — cop
! ο ο

CH \ /

- C-

LiAlHy

in tetrahydrofuran

OH

CH

O O

Vy ΧΙ,

Acetic anhydride

Pyridine

Acetic acid —O ..

-O

Acetic acid see example 2

Ο —CO —CH ₃

OH
O CH

CO-CH,

CO —CH,

Ethyl-methyl-dioxolane,

p-toluenesulfonic acid

O CH-CO-CH ₃

CO-CH,

The (18 -> - 1 Iß) lactone of d, 1-Δ ⁵ -3, 3-ethylenedioxy-II /? - oxy-20-oxo-pregnen-18-acid can be obtained from the in the patent application R 15734 IVb / 12 ο described (18 - »- ll /?) - lactone of d, 1-Δ ⁵ · ¹⁶ -3, 3-ethylenedioxy-li / 3-oxy-20-oxo-pregnadiene-18- acid with a melting point of 242 to 246 ° can be obtained by catalytic hydrogenation of the 16, 17 double bond.

Claims (3)

Patent claims: 1. Process for the preparation of saturated or unsaturated oxygenated steroids of the general formula R ₃ CO - CH ₂ - R ₁ 35 in which R ₁ and R _{2 are} free or functionally modified oxy or oxo groups, R _{3 is} a free or functionally modified oxygenated methyl group and R _{4 is} a free or esterified oxy group, characterized in that saturated or unsaturated pregnane compounds of the general formula are used in a known manner 45 CO-CH, Acetic anhydride Pyridine CH, 0-CO 0 = 1 in which R ₁ , R ₂ and R _{3 have} the meaning given above, is reacted with an oxalic acid ester, the 21-oxalic acid ester obtained is treated in the form of its enol salt with a halogen, the 21-halo-21-oxalic acid ester formed is subjected to acid cleavage 21-halides are converted into the 21-esters or 21-oxy compounds and, if appropriate, in the compounds obtained, introduces a double bond in a 4 (5) division in a known manner, sets functionally modified oxy, oxo or carboxyl groups free and / or oxy groups to oxo groups dehydrated. 2. The method according to claim 1, characterized in that in the 3-position oxygenated 20-oxo-11/9-oxy-pregnane compounds, the remainder of which in the 13-position as a lactonized carboxyl or lactolized aldehyde group with the 11/9 hydroxyl group is present, in particular the (18 -> · ll) -lactone of the zI ⁴ -3,20-dioxo-II /? - oxy-pregnen-18-acid or its functional derivatives, in particular the (18 -> - ll) -lactone the Zl ⁵ -3, 3-ethylenedioxy-20-oxoll / 3-oxy-pregnen-18-acid, the J ⁴ -3, 18,20-trioxole | 5-oxy-pregnen or its 18,11-cyclo-hemiacetal or its functional derivatives, the Δ ⁵ -3,3-ethylenedioxy-II /? - oxy-18, 20-dioxo-preg_nen or its 18,11-cyclo-hemiacetal, the Zl ⁵ -3, 3-ethylenedioxy-20-oxoll / ? -18-dioxypregnene or acetylated, benzoylated or benzylated 18, 11-Cyclohalbacetals des A ^s -3, 3-Äthylenedioxy-llß-oxy-18, 20-dioxo-pregnens used as starting materials. 3. The method according to claim 1, characterized in that one optically active starting products used. 709 759i'426 10.